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Summary The use of uncrewed aerial vehicles (drones) has increased over the last decade. However, their application in healthcare has not been fully examined, in part, due to regulations preventing flight beyond the visual line of sight. This prospective randomised controlled laboratory study aimed to determine whether the in vitro quality of packed red blood cell components is maintained when transported by drone, beyond visual line of sight. Ten identical pairs of packed red blood cell units were randomly allocated to transport by drone or by ground vehicle (1:1, allocation concealment) 68 km between two hospitals in Northumbria, UK. Markers of blood component quality were compared at 8, 14, 28 and 35 days following blood unit manufacture. There was no statistical difference in haemolysis, potassium concentration, total haemoglobin, glucose and lactate, haematocrit and mean cell volume, between the two groups, up to the date of unit expiry. The temperature of the packed red blood cell units did not deviate outside the recommended 2–10°C for transportation, regardless of the allocated group. Blood component transport was faster by drone, but did not reach statistical significance. This study demonstrates the feasibility and safety of flying blood components by drone between hospitals in the United Kingdom. [ABSTRACT FROM AUTHOR]

Summary: The degree of anaemia in sickle cell disease (SCD) is a well‐known contributor to morbidity and mortality. We aimed to explore the factors affecting haemoglobin (Hb) level in African SCD patients, considering haemolysis biomarkers (LDH and bilirubin level, and reticulocyte count), leucocyte and platelet counts and socio‐demographic characteristics (gender, age group, country of residence and BMI). The research was part of the CADRE multinational cohort and involved 3699 SCD patients living in Mali, Senegal, Ivory Coast, Democratic Republic of Congo, Gabon and Cameroon: 2936 SS/Sβ0, 587 SC and 176 Sβ + patients with median Hb level of 8, 11.3 and 11.2 g/dL respectively (p < 0.001). In multivariate analysis conducted in 1394 SS/Sβ0 patients, living in Cameroon, female gender, lower BMI, higher haemolysis markers (especially LDH) and higher leucocyte and platelet counts were independently associated with lower Hb level (all p < 0.05). In 497 SC and 156 Sβ + patients, female gender (p < 0.001), lower BMI (p < 0.05) and higher platelet counts (p < 0.001) were independently associated with lower Hb level. Anaemia in African SCD patients is not only associated with haemolysis but also with the country of residence, lower BMI and leucocyte or platelet counts which might reflect inflammation related to infectious burden in the region. [ABSTRACT FROM AUTHOR]

Summary: Sickle cell disease (SCD) includes a group of heterogenous disorders that result in significant morbidities. HbSS is the most common type of SCD and HbSC is the second most common type of SCD. The prevalence of HbSC disease in the United States and United Kingdom is ~1 in 7174 births and 1 in 6174 births respectively. Despite its frequency, however, HbSC disease has been insufficiently studied and was historically categorized as a more 'mild' form of SCD. We conducted this study of HbSC disease as part of the NHLBI funded Sickle Cell Disease Implementation Consortium (SCDIC). The SCDIC registry included 2282 individuals with SCD, ages 15–45 years of whom 502 (22%) had HbSC disease. Compared with people with sickle cell anaemia (SCA), the study found that people with HbSC disease had a higher frequency of splenomegaly (n (%) = 169 (33.7) vs. 392 (22.1)) and retinopathy (n (%) = 116 (23.1) vs. 189 (10.6)). A Many people with HbSC also had avascular necrosis (n (%) = 112 (22.3)), pulmonary embolism (n (%) = 43 (8.6)) and acute chest syndrome (n (%) = 228 (45.4)) demonstrating significant disease severity. HbSC disease is more clinically severe than was previously recognized and deserves additional evaluation and targeted treatments. [ABSTRACT FROM AUTHOR]

Summary Palpebral conjunctival hue alteration is used in non‐invasive screening for anaemia, whereas it is a qualitative measure. This study constructed machine/deep learning models for predicting haemoglobin values using 150 palpebral conjunctival images taken by a smartphone. The median haemoglobin value was 13.1 g/dL, including 10 patients with <11 g/dL. A segmentation model using U‐net was successfully constructed. The segmented images were subjected to non‐convolutional neural network (CNN)‐based and CNN‐based regression models for predicting haemoglobin values. The correlation coefficients between the actual and predicted haemoglobin values were 0.38 and 0.44 in the non‐CNN‐based and CNN‐based models, respectively. The sensitivity and specificity for anaemia detection were 13% and 98% for the non‐CNN‐based model and 20% and 99% for the CNN‐based model. The performance of the CNN‐based model did not improve with a mask layer guiding the model's attention towards the conjunctival regions, however, slightly improved with correction by the aspect ratio and exposure time of input images. The gradient‐weighted class activation mapping heatmap indicated that the lower half area of the conjunctiva was crucial for haemoglobin value prediction. In conclusion, the CNN‐based model had better results than the non‐CNN‐based model. The prediction accuracy would improve by using more input data with anaemia. [ABSTRACT FROM AUTHOR]

The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS-oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half-life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once-daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601.

Summary: The thrombotic risk with haemoglobin C trait (HbAC) or haemoglobin C disease (HbCC) is unclear. However, individuals with HbCC have demonstrated chronic haemolysis, higher blood viscosity and altered rheology when compared to individuals with wild‐type haemoglobin (HbAA). These physiological alterations may theoretically translate to increased risk of thrombosis; therefore, a systematic literature review was performed to investigate the possible association between HbAC and/or HbCC and thrombosis. Twenty‐two studies met inclusion criteria representing 782 individuals with HbAC (n = 694) or HbCC (n = 88). Fifteen studies described the presence/absence of venous thromboembolism (VTE) in patients with HbAC (n = 685) or HbCC (n = 79), while seven studies described patients with HbAC (n = 9) or HbCC (n = 9) and arterial thrombosis. Most (n = 20) studies were case reports or case series; however, two studies suggested a potential increased VTE risk with HbAC compared to HbAA in (i) all patients (OR 2.2, 95% CI: 0.9–5.5) and in (ii) pregnant individuals (RR 3.7, 95% CI 0.9–16). This review is the largest assessment of patients with HbC trait or disease and thrombosis to date; despite its limitations, the findings suggest HbC may be a predisposing risk factor to thrombosis. Prospective cohort studies are warranted to definitively elucidate the risk of thrombosis in this population. [ABSTRACT FROM AUTHOR]

Summary: We report a large series of 40 patients presenting EPAS1‐mutated paraganglioma (PGL) in whom we investigated a cause underlying chronic hypoxia. Four patients suffered from hypoxaemic heart disease. In patients with available haemoglobin electrophoresis results, 59% presented with a haemoglobin disorder, including six with sickle cell disease, five with sickle cell trait and two with heterozygous haemoglobin C disease. Histological and transcriptomic characterization of EPAS1 tumours revealed increased angiogenesis and high similarities with pseudohypoxic PGLs caused by VHL gene mutations. Sickle haemoglobinopathy carriers could thus be at increased risk for developing EPAS1‐PGLs, which should be taken into account in their management and surveillance. [ABSTRACT FROM AUTHOR]

Summary: We evaluated the impact of peer reviews in driving improvement in healthcare quality for people with haemoglobinopathy in the United Kingdom. We analysed compliance to four Quality Standards (QS)‐based peer reviews from 2010 to 2020 to evaluate its impact in driving healthcare quality. Seventeen paediatric and 29 adult haemoglobinopathy centres were reviewed in 2010/11 and 2012/13 respectively; 33 paediatric and 33 adult centres were reviewed in 2014/16, and 32 paediatric and 32 adult centres were reviewed in 2018/2020. Compliance with QS and participant feedback were analysed to assess the impact of peer review programmes to drive improvement in quality of care. We noted that haemoglobinopathy centres significantly improved their compliance to QS between the first two review programmes, but not in the final review programme. In comparison to other disease‐group reviews, the haemoglobinopathy departments were less able to address critical peer review recommendations in their own institutions. The peer review programme was unable to drive sustained improvement in healthcare quality, underscoring the need for sustained development and support for haemoglobinopathy services in the National Health Service. Further work is needed to understand why disparities exist among peer review‐driven improvement initiatives within different disease groups. [ABSTRACT FROM AUTHOR]

Accurate laboratory screening for sickle cell disease and other haemoglobin disorders is expanding worldwide. Two new reports describe different methods and strategies for screening in Mali and Denmark, respectively, and their encouraging results suggest that countries should tailor their screening programmes according to local needs, resources and opportunities. Commentary on: Guindo et al. Potential for a large‐scale newborn screening strategy for sickle cell disease in Mali: a comparative diagnostic performance study of two rapid diagnostic tests (SickleScan® and HemotypeSC®) on cord blood. Br J Haematol 2024;204:337–345 and Gravholt et al. The Danish national haemoglobinopathy screening programme: report from 16 years of screening in a low‐prevalence, non‐endemic region. Br J Haematol 2024;204:329–336. [ABSTRACT FROM AUTHOR]

The study of Ellsworth et al. (Br J Haematol, 2024) demonstrated the usefulness of oxygen gradient ektacytometry technique to better identify the physiological parameters that could increase the risk of sickling of red blood cells (RBCs) from sickle cell trait (SCT) carriers. Oxygen gradient ektacytometry combined with pH and osmolality modulations could help in identifying SCT carriers at risk for kidney disorders or exercise‐related complications. Other factors than the percentages of haemoglobin S are probably involved in the propensity of RBCs from SCT carriers to sickle during deoxygenation.Commentary on: Ellsworth et al. Hypertonicity and/or acidosis induce marked rheological changes under hypoxic conditions in sickle trait red blood cells. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19669. [ABSTRACT FROM AUTHOR]

Historically understudied and regarded as a mild type of sickle cell disease, HbSC can be associated with significant, progressive complications. Prospective studies are urgently needed to address treatment gaps for HbSC disease. Commentary on: Nelson et al. The clinical spectrum of HbSC sickle cell disease‐not a benign condition. Br J Haematol 2024;205:653‐663. [ABSTRACT FROM AUTHOR]

Impaired respiratory function reduces haemoglobin oxygen affinity in COVID-19 Keywords: COVID-19; haemoglobin-oxygen affinity; haemoglobin P50; oxyhaemoglobins; PaO2 to fraction of inspired oxygen ratio; SARS-CoV-2 EN COVID-19 haemoglobin-oxygen affinity haemoglobin P50 oxyhaemoglobins PaO2 to fraction of inspired oxygen ratio SARS-CoV-2 e44 e47 4 02/21/23 20230301 NES 230301 Using homology modelling and molecular docking algorithms, Liu and Li predicted the existence of interactions between SARS-Cov-2 and haemoglobin (Hb) and suggested that these interactions may change haemoglobin-oxygen (Hb-O SB 2 sb ) affinity.[1] Hb-O SB 2 sb affinity has been extensively studied in intensive care unit (ICU) patients with COVID-19 (usually intubated and mechanically ventilated) showing normal to increased affinity.[[2], [4]] Higher Hb-O SB 2 sb affinity facilitates Hb oxygenation in the lungs while reducing tissue O SB 2 sb unloading; a reduced Hb-O SB 2 sb affinity has the opposite effect. COVID-19, haemoglobin-oxygen affinity, haemoglobin P50, oxyhaemoglobins, PaO2 to fraction of inspired oxygen ratio, SARS-CoV-2. [Extracted from the article]

Keywords: methemoglobinemia; m-hemoglobin; riboflavin; unstable hemoglobin EN methemoglobinemia m-hemoglobin riboflavin unstable hemoglobin 385 388 4 01/23/23 20230201 NES 230201 Methaemoglobinaemia is a rare condition characterised by an excess of a form of haemoglobin (Hb) in which the iron cation of haeme is in the +3 (ferric) oxidation state instead of the +2 (ferrous) state.[1] Methaemoglobin (MetHb) is unable to properly release oxygen and induces tissue hypoxia.[1] Acquired forms are the most common and result from exposure to oxidising agents.[2] Hereditary forms are either "enzymatic", due to a deficiency in cytochrome b5 reductase (CYB5R), the main enzyme involved in the physiological reduction of MetHb to Hb, or related to globin structural abnormalities responsible for haeme iron auto-oxidation (HbM disease and unstable Hb).[3], [4], [5] Clinical presentation varies according to aetiology, kinetics and MetHb level, ranging from asymptomatic cases to life-threatening symptoms. Hemoglobin Haná Nebo alpha 2 beta 2 63 (E7) his-Asn: nová nestabilní varianta hemoglobinu s paradoxne rozdílnou klinickou manifestací u kuráku a nekuráku téze rodiny [hemoglobin Haná or alpha 2 beta 2 63 (E7) his-Asn: a new unstable hemoglobin variant with a paradoxically different clinical manifestations in smokers and non-smokers in the same family]. [Extracted from the article]

One purpose of red cell transfusion is to increase the haemoglobin concentration in the patient's bloodstream.[1] Transfusion of red cell units donated by individuals with hereditary haemochromatosis (HH) remains controversial. HH donors were on average older, with male preponderance, and more often repeat donors (Table 1), which may all be common features of HH donors, and may likely contribute to improving haemoglobin increments in patients transfused with red cell units from HH donors. [Extracted from the article]

Summary: Lung damage caused by SARS‐Cov‐2 virus results in marked arterial hypoxia, accompanied in many cases by hypocapnia. The literature is inconclusive as to whether these conditions induce alteration of the affinity of haemoglobin for oxygen. We studied the oxyhaemoglobin dissociation curves (ODCs) of 517 patients hospitalized with coronavirus disease 2019 (COVID‐19) for whom arterial blood gas analysis (BGA) was performed upon hospitalization (i.e., before treatment). With respect to a conventional normal p50 (pO2 at 50% saturation of haemoglobin) of 27 mmHg, 76% had a lower standardized p50 (p50s) and 85% a lower in vivo p50 (p50i). In a 33‐patient subgroup with follow‐up BGAs after 3, 6, 9, 12, 15 and 18 days' treatment, p50s and p50i exhibited statistically significant differences between baseline values and values recorded at all these time points. The 30‐day Kaplan–Meier survival curves of COVID‐19 patients stratified by p50i level show a higher probability of survival among patients who at admission had p50 values below 27 mmHg (p = 0.012). Whether the observed alteration of the affinity of haemoglobin for oxygen in COVID‐19 patients is a direct or indirect effect of the virus on haemoglobin is unknown. [ABSTRACT FROM AUTHOR]

Summary: Blood donors are at risk of iron deficiency anaemia. While this risk is decreased through ferritin‐based deferral, ideally ferritin monitoring should also aid in optimising donation frequencies. We extended an existing model of haemoglobin (Hb) synthesis with iron homeostasis and validated the model on a cohort of 300 new donors whose ferritin levels were measured from stored blood samples collected over a 2‐year period. We then used the donor's gender, body weight, height, and baseline Hb and ferritin levels to predict subsequent Hb and ferritin levels. The prediction error was within measurement variability in 88% of Hb level predictions and 64% of ferritin level predictions. A sensitivity analysis of the model revealed that baseline ferritin level was the most important in predicting future ferritin levels. Finally, we used the model to calculate the annual donation frequency at which donors would keep their ferritin level >15 ng/ml when measured after donating for 2 years. The mean annual donation frequency would then be 1.9 for women and 4.1 for men. The computational model, requiring baseline values only, can predict future Hb and ferritin levels remarkably well. This enables determination of optimal donation frequencies for individual donors at the start of their donation career. [ABSTRACT FROM AUTHOR]

Summary: The objective of the study was to compare the maternal and foetal outcomes of pregnancies complicated by Hb H‐constant spring (HbH‐CS) disease/deletional HbH (HbH‐del) disease and low‐risk pregnancies. A retrospective cohort research was undertaken on singleton pregnancies with Hb H‐CS and Hb H‐del diseases. The controls were randomly selected with a control‐to‐case ratio of 10:1. A total of 55 cases of HbH‐CS disease, 231 cases of HbH‐del disease and 2860 controls were compared. The mean gestational age at delivery and birthweight were significantly lower in the HbH‐CS group than in the HbH‐del and control groups. The clinical course of Hb H‐CS was more severe than that of HbH‐del disease. The rates of preterm birth, foetal growth restriction and low birthweight were significantly increased in the HbH‐CS and Hb H‐del groups. These rates were significantly greater in the HbH‐CS group than in the H‐del group. The maternal outcomes were not significantly different among the three groups. In conclusion, pregnancy worsens the course of HbH disease, more noticeably in HbH‐CS disease. Hb H disease significantly increases the risk of adverse foetal outcomes, more noticeably in the HbH‐CS group. Pregnancy is relatively safe for women with HbH disease. [ABSTRACT FROM AUTHOR]

Summary: Owing to the unique pathophysiology of anaemia in haemoglobin Bart's hydrops fetalis (HBHF), a transfusion strategy based on beta‐thalassemia guidelines is suboptimal for chronically transfused HBHF patients. A more aggressive transfusion aimed at reducing the proportion of non‐functional HbH and improving the "functional" haemoglobin (f‐Hb) can lead to reduced haemolysis and improved tissue oxygenation. However, the optimal transfusion targets for these parameters are not yet defined. In this retrospective, longitudinal study on four chronically transfused patients with HBHF, we used receiver operating characteristic curves to find a pre‐transfusion f‐Hb of 106 g/l and a HbH of 16.1% to be the optimal thresholds to achieve a normal soluble transferrin receptor and lactate dehydrogenase, respectively. [ABSTRACT FROM AUTHOR]

Summary: Sickle cell disease (SCD) is a genetic disorder that affects millions around the world. Enhancement of fetal γ‐globin levels and fetal haemoglobin (HbF) production in SCD patients leads to diminished severity of many clinical features of the disease. We recently identified the transcriptional co‐activator PGC‐1α as a new protein involved in the regulation of the globin genes. Here, we report that upregulation of PGC‐1α by infection with a lentivirus expressing PGC‐1α or by the small‐molecule PGC‐1α agonist ZLN005 in human primary erythroid progenitor CD34+ cells induces both fetal γ‐globin mRNA and protein expression as well as the percentage of HbF‐positive cell (F cells) without significantly affecting cell proliferation and differentiation. We further found that the combination of ZLN005 and hydroxyurea (hydroxycarbamide) exhibited an additive effect on the expression of γ‐globin and the generation of F cells from cultured CD34+ cells. In addition, ZLN005 induced robust expression of the murine embryonic βh1‐globin gene and to a lesser extent, human γ‐globin gene expression in sickle mice. These findings suggest that activation of PGC‐1α by ZLN005 might provide a new path for modulating HbF levels with potential therapeutic benefit in β‐hemoglobinopathies. [ABSTRACT FROM AUTHOR]

In the not so distant past, pregnancy in thalassaemia patients was considered a very high risk and often not recommended. The results regarding alpha‐thalassaemia and in particular haemoglobin H disease by Srimeuniwai and colleagues are very encouraging. Nowadays thalassaemic women not only become pregnant, but maternal outcome is not decreased compared to controls. Commentary on: Ake‐sittipaisarn, et al. Outcomes of pregnancies complicated by haemoglobin H‐Constant Spring and deletional haemoglobin H disease: A retrospective cohort study. Br J Haematol 2022;199:122–129. [ABSTRACT FROM AUTHOR]

Summary: Re‐activation of fetal haemoglobin (HbF) has been proved to be an effective strategy for the treatment of β‐haemoglobinopathies. In this study, we identified TEA domain transcription factor 4 (TEAD4) as a new potential regulator of HbF by integrating public data sets with quantitative polymerase chain reaction analysis in β‐thalassaemia patients. Significant negative correlation was observed between the expression of TEAD4 and HbF levels in β‐thalassaemia patients. Functional validations of TEAD4 inhibition in both β‐thalassaemia CD34+ cells and HUDEP‐2 cells indicated that depletion of TEAD4 led to a significant increase of HbF. Finally, we identified a binding motif of TEAD4 on γ‐globin gene promoters; its disruption consistently led to de‐repression of HbF. Taken together, these results demonstrate that TEAD4 could act as a transcriptional inhibitor of the γ‐globin gene through direct binding on its promoter. Our findings demonstrate a novel role of TEAD4 on the regulation of HbF, which may benefit patients with β‐haemoglobinopathies. [ABSTRACT FROM AUTHOR]

Summary: Alleviating anaemia in patients with sickle cell disease (SCD) is crucial in managing acute complications, mitigating end‐organ damage and preventing early mortality. Some disease‐modifying and curative therapies have increased haemoglobin (Hb) levels to exceed 100 g/l, a threshold above which complications from red blood cell (RBC) transfusions have occurred, raising concern about whole‐blood viscosity‐related complications with these therapies. Here we discuss the rationale behind this limit, the effect of viscosity on blood flow and the applicability of this Hb threshold to therapies for SCD beyond RBC transfusions. [ABSTRACT FROM AUTHOR]

Summary: Hydroxyurea (hydroxycarbamide) is an effective treatment for sickle cell anaemia (SCA), but clinical responses depend primarily upon the degree of fetal haemoglobin (HbF) induction and the heterogeneity of HbF expression across erythrocytes. The number and characteristics of HbF‐containing cells (F‐cells) are not assessed by traditional HbF measurements. Conventional hydroxyurea dosing (e.g. fixed doses or low starting doses with stepwise escalation) produces a moderate heterocellular HbF induction, but haemolysis and clinical complications continue. Robust, pancellular HbF induction is needed to minimise or fully inhibit polymerisation of sickle haemoglobin. We treated children with hydroxyurea using an individualised, pharmacokinetics‐guided regimen starting at predicted maximum tolerated dose (MTD). We observed sustained HbF induction (mean >30%) for up to 6 years, which was not dependent on genetic determinants of HbF expression. Nearly 70% of patients had ≥80% F‐cells (near‐pancellular), and almost half had ≥90% F‐cells (pancellular). The mean HbF/F‐cell content was ~12 pg. Earlier age of initiation and better medication adherence were associated with high F‐cell responses. In summary, early initiation of hydroxyurea using pharmacokinetics‐guided starting doses at predicted MTD can achieve sustained near‐pancellular or pancellular HbF expression and should be considered an achievable goal for children with SCA treated with hydroxyurea at optimal doses. Clinical trial registration number: NCT02286154 (clinicaltrials.gov). [ABSTRACT FROM AUTHOR]

Keywords: fetal haemoglobin; sickle cell; gene expression; haplotype EN fetal haemoglobin sickle cell gene expression haplotype e61 e64 4 07/19/21 20210715 NES 210715 Compared with other common haplotypes of the sickle haemoglobin (HbS) gene, fetal haemoglobin (HbF) levels are highest in the Arab-Indian haplotype. A unique I HBB i subhaplotype and variants of the I ATXR1 i gene were associated with HbF only in the Arab-Indian haplotype (for a review see14). [Extracted from the article]

Summary: Reactivation of fetal haemoglobin (HbF) expression is an effective way to treat β‐thalassaemia and sickle cell anaemia. In the present study, we identified a novel GATA zinc finger domain‐containing protein 2A (GATAD2A) mutation, which contributed to the elevation of HbF and ameliorated clinical severity in a patient with β‐thalassaemia, by targeted next‐generation sequencing. Knockout of GATAD2A led to a significant induction of HbF in both human umbilical cord blood‐derived erythroid progenitor‐2 (HUDEP‐2) and human cluster of differentiation (CD)34+ cells with a detectable impact on erythroid differentiation. Furthermore, heterozygous knockout of GATAD2A impaired recruitment of chromodomain helicase DNA‐binding protein 4 (CHD4) to the methyl‐binding domain protein 2 (MBD2)‐containing nucleosome remodelling and deacetylation (NuRD) complex. Our present data suggest that mutations causing the haploinsufficiency of GATAD2A might contribute to amelioration of clinical severity in patients with β‐thalassaemia. [ABSTRACT FROM AUTHOR]

Summary: Increasing evidence suggests that free haem and iron exert vasculo‐toxic and pro‐inflammatory effects by activating endothelial and immune cells. In the present retrospective study, we compared serum samples from transfusion‐dependent patients with β‐thalassaemia major and intermedia, hereditary spherocytosis and sickle cell disease (SCD). Haemolysis, transfusions and ineffective erythropoiesis contribute to haem and iron overload in haemolytic patients. In all cohorts we observed increased systemic haem and iron levels associated with scavenger depletion and toxic 'free' species formation. Endothelial dysfunction, oxidative stress and inflammation markers were significantly increased compared to healthy donors. In multivariable logistic regression analysis, oxidative stress markers remained significantly associated with both haem‐ and iron‐related parameters, while soluble vascular cell adhesion molecule 1 (sVCAM‐1), soluble endothelial selectin (sE‐selectin) and tumour necrosis factor α (TNFα) showed the strongest association with haem‐related parameters and soluble intercellular adhesion molecule 1 (sICAM‐1), sVCAM‐1, interleukin 6 (IL‐6) and vascular endothelial growth factor (VEGF) with iron‐related parameters. While hereditary spherocytosis was associated with the highest IL‐6 and TNFα levels, β‐thalassaemia major showed limited inflammation compared to SCD. The sVCAM1 increase was significantly lower in patients with SCD receiving exchange compared to simple transfusions. The present results support the involvement of free haem/iron species in the pathogenesis of vascular dysfunction and sterile inflammation in haemolytic diseases, irrespective of the underlying haemolytic mechanism, and highlight the potential therapeutic benefit of iron/haem scavenging therapies in these conditions. [ABSTRACT FROM AUTHOR]

Keywords: Senicapoc; sickle cell anaemia; voxelotor EN Senicapoc sickle cell anaemia voxelotor e129 e132 4 02/24/21 20210301 NES 210301 In 2011, the I British Journal of Haematology i published the results of the Phase III study for senicapoc in sickle cell disease (SCD).1 Despite encouraging improvements of biomarkers indicating decreased haemolysis and improved anaemia, the study failed to show changes in acute painful crises, the primary clinical endpoint of the trial. Although 145 patients were treated with senicapoc (61 without and 84 with HC), due to the premature termination of the trial, only 85 were treated for at least 24 weeks: Hb response was observed in 34% of the patients treated with senicapoc (29/85), with a 36% response in patients treated with senicapoc plus HU (21/59), 31% response in patients treated with senicapoc alone (eight of 26), whereas only 6% of the patients in the placebo group (five of 85) showed a Hb response. The Hb response was also evaluated in the voxelotor trial as the percentage of patients with Hb values of >=100 g/l at week 24: using this definition, 42-4% (36/85) of all senicapoc-treated patients, 46-2% (12/26) of patients treated with senicapoc alone, and 40-7% (24/59) of patients treated with senicapoc plus HC showed a response. Panel C: Waterfall plot of change in Hb values from baseline to week 24 for the 59 patients treated with senicapoc and hydroxycarbamide (HC), the 26 patients treated with senicapoc alone, the 53 placebo patients treated with HC and the 32 placebo patients receiving no other treatment. [Extracted from the article]

Haemoglobin H (HbH) disease is a type of non‐transfusion‐dependent thalassaemia. This cross‐sectional study aimed at determining the prevalence and severity of liver iron overload and liver fibrosis in patients with HbH disease. Risk factors for advanced liver fibrosis were also identified. A total of 80 patients were evaluated [median (range) age 53 (24–79) years, male 34%, non‐deletional HbH disease 24%]. Patients underwent 'observed' T2‐weighted magnetic resonance imaging examination for liver iron concentration (LIC) quantification, and transient elastography for liver stiffness measurement (LSM) and fibrosis staging. In all, 25 patients (31%) had moderate‐to‐severe liver iron overload (LIC ≥7 mg/g dry weight). The median LIC was higher in non‐deletional than in deletional HbH disease (7·8 vs. 2.9 mg/g dry weight, P = 0·002). In all, 16 patients (20%) had advanced liver fibrosis (LSM >7.9 kPa) and seven (9%) out of them had probable cirrhosis (LSM >11.9 kPa). LSM positively correlated with age (R = 0·24, P = 0·03), serum ferritin (R = 0·36, P = 0·001) and LIC (R = 0·28, P = 0·01). In multivariable regression, age ≥65 years [odds ratio (OR) 4·97, 95% confidence interval (CI) 1·52–17·50; P = 0·047] and moderate‐to‐severe liver iron overload (OR 3·47, 95% CI 1·01–12·14; P = 0·01) were independently associated with advanced liver fibrosis. The findings suggest that regular screening for liver complications should be considered in the management of HbH disease. [ABSTRACT FROM AUTHOR]

Biallelic pathogenic variants in CAD, that encode the multienzymatic protein required for de-novo pyrimidine biosynthesis, cause early infantile epileptic encephalopathy-50. This rare disease, characterized by developmental delay, intractable seizures and anaemia, is amenable to treatment with uridine. We present a patient with macrocytic anaemia, elevated haemoglobin-A2 levels, anisocytosis, poikilocytosis and target cells in the blood smear, and mild developmental delay. A next-generation sequencing panel revealed biallelic variants in CAD. Functional studies did not support complete abrogation of protein function; however, the patient responded to uridine supplement. We conclude that biallelic hypomorphic CAD variants may cause a primarily haematological phenotype., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Summary: Repeated red blood cell (RBC) transfusions in preterm neonates are associated with poor outcome and increased risk for prematurity‐associated diseases. RBC transfusions cause the progressive replacement of fetal haemoglobin (HbF) by adult haemoglobin (HbA). We monitored HbF levels in 25 preterm neonates until 36 weeks of post‐menstrual age (PMA); patients received RBC units from allogeneic cord blood (cord‐RBCs) or from adult donors (adult‐RBCs), depending on whether cord‐RBCs were available. Primary outcome was HbF level at PMA of 32 weeks. Twenty‐three neonates survived until this age: 14 received no transfusions, two only cord‐RBCs, three only adult‐RBCs and four both RBC types. HbF levels in neonates transfused with cord‐RBCs were significantly higher than in neonates receiving adult‐RBCs (P < 0·0001) or both RBC types (P < 0·0001). Superimposable results were obtained at PMA of 36 weeks. Every adult‐RBCs transfusion increased the risk for an HbF in the lowest quartile by about 10‐fold, whereas this effect was not evident if combined adult‐ and cord‐RBCs were evaluated. Overall, these data show that transfusing cord‐RBCs can limit the HbF depletion caused by conventional RBC transfusions. Transfusing cord blood warrants investigation in randomised trials as a strategy to mitigate the severity of retinopathy of prematurity (NCT03764813). [ABSTRACT FROM AUTHOR]

Frequent blood donors become iron deficient. HFE mutations are present in over 30% of donors. A 24-month study of 888 first time/reactivated donors and 1537 frequent donors measured haemoglobin and iron status to assess how HFE mutations impact the development of iron deficiency erythropoiesis. Donors with two HFE mutations had increased baseline haemoglobin and iron stores as did those with one mutation, albeit to a lesser extent. Over multiple donations haemoglobin and iron status of donors with HFE mutations paralleled those lacking mutations. The prevalence of HFE mutations was not increased in higher intensity donors. Thus, in general, HFE mutations do not temper donation-induced changes in haemoglobin and iron status. However, in Black donors there was an increase of H63D carriers at baseline, from 3·7% in first time/reactivated donors to 15·8% in frequent donors, suggesting that the relative effects of HFE mutations on iron absorption may vary between racial/ethnic groups. In secondary analyses, venous haemoglobin decreased more slowly in donors with ferritin ≥12μg/l; and haemoglobin recovery time was shorter in donors with reticulocyte haemoglobin (CHr) ≥32·6pg, indicating that these biochemical measures are better indicators of a donor's response to phlebotomy than their HFE mutation status.

Keywords: fetal haemoglobin induction; -thalassaemia/HbE; pomalidomide; hydroxyurea; decitabine EN fetal haemoglobin induction -thalassaemia/HbE pomalidomide hydroxyurea decitabine e240 e245 6 06/18/20 20200615 NES 200615 Studies have shown that increased expression of fetal haemoglobin (HbF; SB 2 sb SB 2 sb ) can ameliorate red blood cell deficiencies in patients with -thalassaemia and sickle cell disease (SCD).[[1], [3]] Pharmacological induction of HbF expression in -thalassaemia has been investigated using several classes of small molecules,[4] including 5-azacytidine,[5] decitabine,[6] hydroxyurea,[7] LSD1 inhibitors (tranylcypromine and RN-1),[[8]] and short chain fatty acid derivatives.[[10]] Among these molecules, hydroxyurea is the only U.S. Food and Drug Administration (FDA) currently approved drug for the treatment of SCD and/or -thalassaemia. SP 0 sp -thalassaemia/HbE precursors from patients of different SP 0 sp -thalassemic mutations (Table SI) showed similarly increased levels of HbF induction in response to pomalidomide treatment. GLO:1XW/15jun20:bjh16670-fig-0002.jpg PHOTO (COLOR): 2 Effect of pomalidomide and its combinations on erythroid differentiation and mRNA expression of HbF regulators in cultured erythroid cells from 0-thalassaemia/HbE patients. HbF-inducing effects of hydroxyurea (HU), decitabine (DAC), and RN-1 in erythroid cells from 0-thalassaemia/HbE patients. [Extracted from the article]

Switching from dispersible to film coated tablet formulation of deferasirox improves hemoglobin levels and transfusional interval in patients with transfusion-dependent-thalassemia Keywords: transfusion-dependent thalassemia; iron chelation therapy; dispersible-tablet deferasirox; film-coated-tablet deferasirox; switch EN transfusion-dependent thalassemia iron chelation therapy dispersible-tablet deferasirox film-coated-tablet deferasirox switch e60 e63 4 04/15/20 20200415 NES 200415 Current treatment options for transfusion-dependent-thalassemia (TdT) are mostly limited to managing anaemia with regular red blood cell (RBC) transfusions and its complications, including iron overload (Taher & Saliba, [7]), with a life expectancy that in recent years extends beyond 40 years of age (Iolascon I et al. i , [3]). Transfusion-dependent thalassemia, iron chelation therapy, dispersible-tablet deferasirox, film-coated-tablet deferasirox, switch. [Extracted from the article]

Summary: Optimal red cell transfusion support in myelodysplastic syndromes (MDS) has not been tested and established. The aim of this study was to demonstrate feasibility of recruitment and follow‐up in an outpatient setting with an exploratory assessment of quality of life (QoL) outcomes (EORTC QLQ‐C30 and EQ‐5D‐5L). We randomised MDS patients to standardised transfusion algorithms comparing current restrictive transfusion thresholds (80 g/l, to maintain haemoglobin 85–100 g/l) with liberal thresholds (105 g/l, maintaining 110–125 g/l). The primary outcomes were measures of compliance to transfusion thresholds. Altogether 38 patients were randomised (n = 20 restrictive; n = 18 liberal) from 12 participating sites in UK, Australia and New Zealand. The compliance proportion for the intention‐to‐treat population was 86% (95% confidence interval 75–94%) and 99% (95–100%) for restrictive and liberal arms respectively. Mean pre‐transfusion haemoglobin concentrations for restrictive and liberal arms were 80 g/l (SD6) and 97 g/l (SD7). The total number of red cell units transfused on study was 82 in the restrictive and 192 in the liberal arm. In an exploratory analysis, the five main QoL domains were improved for participants in the liberal compared to restrictive arm. Our findings support the feasibility and need for a definitive trial to evaluate the effect of different red cell transfusion thresholds on patient‐centred outcomes. [ABSTRACT FROM AUTHOR]

Recurrent vaso-occlusive crises resulting in bone infarction constitute the main cause of osteonecrosis in patients with sickle cell anaemia (SCA) (da Silva Junior I et al., i [10]). Patients with ANXA2*5681 AA genotype (22%, 95% CI: 16-31%) had a significantly higher osteonecrosis development rate compared to patients with non-AA genotype (6%, 95% CI: 4-11%) (P < 0-0001). Genetic assessment of the ANXA2*5681 polymorphism (rs7170178) distribution revealed 44/85 patients (52%) harbouring the ANXA2*5681 non-AA genotype and 41/85 (48%) carrying the ANXA2*5681 AA genotype. To examine the biological impact of I ANXA2 i *5681 polymorphism (rs7170178) at the transcriptional and translational levels, we evaluated 85 new freshly collected samples from patients with SCA who developed (26 patients) or did not develop (59 patients) osteonecrosis. [Extracted from the article]

Summary: We investigated neural correlates of cognitive function in adults with beta thalassaemia major (β‐TM) compared to healthy controls using scalp‐recorded event‐related potentials (ERPs). Event‐related potential studies in the field of β‐TM are scarce and mostly limited to children. A stop‐signal task was used to evaluate indices of attention and response inhibition function, considered to be the hallmark of executive control. Correlations between task performance, ERPs and haemoglobin were also examined. Results showed impaired cognitive performance in β‐TM patients, as indicated by longer response times than controls. Haemoglobin was negatively correlated with response times to Go stimuli. Electrophysiological results indicated significant β‐TM‐related alterations in neuronal activity, reflected in greater peak amplitudes of several task‐related ERP components. A possible interpretation of these ERP results is that β‐TM patients need to recruit additional brain resources when dealing with cognitive challenge. Significant correlations were found between levels of haemoglobin and amplitude of all ERP components; the lower the haemoglobin, the more pronounced the ERPs amplitude. The present study represents a novel investigation of cognitive function and related brain dynamics in β‐TM in adult. Integrating neuropsychological assessment and interventions into traditional disease management, may be imperative in achieving a better quality of life for these patients. [ABSTRACT FROM AUTHOR]

We present a nationwide prospective Swedish registry‐based study of Waldenström macroglobulinaemia (WM), that focuses on incidence and survival in relation to clinical prognostic factors and primary systemic therapies. A total of 1511 patients with WM and lymphoplasmocytic lymphoma (LPL) were registered in the Swedish Lymphoma Registry (SLR) between 1 January 2000 and 31 December 2014. The age‐adjusted incidence of WM/LPL was 11·5 per million persons per year, three times higher than the reported incidence worldwide. Medical records were retrieved for 1135 patients (75%). A retrospective review showed that 981 (86·1%) of these patients fulfilled the World Health Organization diagnostic criteria for WM and these patients were analysed further. The overall survival (OS) improved between two periods – 2000–2006 and 2007–2014 – with a five‐year OS of 61% and 70%, respectively. Significant prognostic factors for OS, evaluated at the time of diagnosis, were age, elevated lactate dehydrogenase level and haemoglobin ≤115 g/l for patients receiving therapy 0–3 months after diagnosis, and age, poor performance status, haemoglobin ≤115 g/l, and female sex in "watch and wait" patients (multivariable analysis). The level of the IgM monoclonal immunoglobulin had no significant prognostic value. Rituximab included in first‐line therapy was associated with improved survival. [ABSTRACT FROM AUTHOR]

Clinical expression of sickle cell disease (SCD) often shows considerable variation, such as the severity of anaemia, the frequency of painful vaso-occlusive crises, kidney dysfunctions, stroke, acute chest syndrome and mortality. Indeed, only one GWAS on HbF in SCD has been performed in patients in Africa (from Tanzania)14 and had replicated variants in two known HbF promoting loci, that is, I HBS1L-MYB i and I BCL11A i . DNA polymorphisms at the BCL11A, HBS1L-MYB, and -globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. [Extracted from the article]

Microcytosis in patients with haemoglobin C trait: is -thalassaemia trait to blame? Keywords: haemoglobinopathies; haemoglobin C trait; microcytosis; HbC trait; -thalassaemia trait EN haemoglobinopathies haemoglobin C trait microcytosis HbC trait -thalassaemia trait e129 e131 3 12/07/20 20201201 NES 201201 Haemoglobin C (HbC) is the third most common variant haemoglobin worldwide after haemoglobin S and E. In some regions of West Africa, the allele frequency is >20%.1 The -globin Glu6Lys substitution decreases HbC solubility, causing sickle cell disease when co-inherited with haemoglobin S. However, HbC trait is asymptomatic and displays normal haemoglobin concentration. Haemoglobinopathies, haemoglobin C trait, microcytosis, HbC trait, -thalassaemia trait. [Extracted from the article]

The article focuses on a study related to prefibrotic versus overtly fibrotic primary myelofibrosis. Topics discussed include presence of higher hemoglobin, higher platelet count, higher incidence of thrombocytosis in pre-primary myelofibrosis; lower incidence of splenomegaly; and WHO-defined diagnosis of early/prefibrotic primary myelofibrosis.

Summary: Cardiac involvement is well characterized in sickle cell anaemia (SCA) but cardiac features associated with Haemoglobin SC (HbSC) disease are mostly unknown. We compared 60 patients with HbSC disease (median age 31 years, 25 men) to 60 SCA patients and 60 controls matched for age and gender. Left ventricular ejection fraction (LVEF), left ventricle (LV) mass index (LVMi), cardiac index and peak tricuspid regurgitation velocity (TRV) were measured using echocardiography. LV filling pressures were assessed using the ratio of early diastolic transmitral velocity to tissue velocity (E/e’ ratio). The LVMi was higher in both genotypes compared to controls. However, whereas LV hypertrophy was observed only in 3(5%) HbSC patients, this condition was diagnosed in 27(45%) SCA patients (P < 0·0001). While cardiac index and TRV were similar in HbSC compared to controls, SCA patients exhibited elevated cardiac output and TRV. LVEF was similar in the 3 groups. However, both genotypes had a higher E/e’ ratio compared to controls. Cardiac involvement in SCA was related to anaemia and haemolysis, while LV diastolic dysfunction and TRV in HbSC disease patients were related to arterial hypertension and overweight comorbidities. In summary, cardiac involvement and its determinants are different in HbSC disease and SCA. Patient's genotype should be considered with regard to the echocardiographic indications and findings. [ABSTRACT FROM AUTHOR]

The major β-haemoglobinopathies, sickle cell disease and β-thalassaemia, represent the most common monogenic disorders worldwide and a steadily increasing global disease burden. Allogeneic haematopoietic stem cell transplantation, the only curative therapy, is only applied to a small minority of patients. Common clinical management strategies act mainly downstream of the root causes of disease. The observation that elevated fetal haemoglobin expression ameliorates these disorders has motivated longstanding investigations into the mechanisms of haemoglobin switching. Landmark studies over the last decade have led to the identification of two potent transcriptional repressors of γ-globin, BCL11A and ZBTB7A. These regulators act with additional trans-acting epigenetic repressive complexes, lineage-defining factors and developmental programs to silence fetal haemoglobin by working on cis-acting sequences at the globin gene loci. Rapidly advancing genetic technology is enabling researchers to probe deeply the interplay between the molecular players required for γ-globin (HBG1/HBG2) silencing. Gene therapies may enable permanent cures with autologous modified haematopoietic stem cells that generate persistent fetal haemoglobin expression. Ultimately rational small molecule pharmacotherapies to reactivate HbF could extend benefits widely to patients. [ABSTRACT FROM AUTHOR]

Summary: Fetal haemoglobin (HbF, α2γ2) induction has long been an area of investigation, as it is known to ameliorate the clinical complications of sickle cell disease (SCD). Progress in identifying novel HbF‐inducing strategies has been stymied by limited understanding of gamma (γ)–globin regulation. Genome‐wide association studies (GWAS) have identified variants in BCL11A and HBS1L‐MYB that are associated with HbF levels. Functional studies have established the roles of BCL11A, MYB, and KLF1 in γ–globin regulation, but this information has not yielded new pharmacological agents. Several drugs are under investigation in clinical trials as HbF‐inducing agents, but hydroxycarbamide remains the only widely used pharmacologic therapy for SCD. Autologous transplant of edited haematopoietic stem cells holds promise as a cure for SCD, either through HbF induction or correction of the causative mutation, but several technical and safety hurdles must be overcome before this therapy can be offered widely, and pharmacological therapies are still needed. [ABSTRACT FROM AUTHOR]

The study objectives were to examine the association of maternal haemoglobin with stillbirth and perinatal death in a multi-ethnic population in England. We conducted a retrospective cohort analysis using anonymised maternity data from 14 001 women with singleton pregnancies ≥24 weeks’ gestation giving birth between 2013 and 2015 in two hospitals - the Royal Wolverhampton NHS Trust and Guy's and St Thomas’ NHS Foundation Trust. Multivariable logistic regression analyses were undertaken to analyse the associations between maternal haemoglobin at first visit and at 28 weeks with stillbirth and perinatal death, adjusting for 11 other risk factors. Results showed that 46% of the study population had anaemia (haemoglobin <110 g/l) at some point during their pregnancy. The risk of stillbirth and perinatal death decreased linearly per unit increase in haemoglobin concentration at first visit (adjusted odds ratio [aOR] stillbirth = 0·70, 95% confidence interval [CI] 0·58–0·85, aOR perinatal death = 0·71, 95% CI 0·60–0·84) and at 28 weeks (aOR stillbirth = 0·83, 95% CI 0·66–1·04; aOR perinatal death = 0·86, 95%CI 0·67–1·12). Compared with women with haemoglobin ≥110 g/l, the risk of stillbirth and perinatal death was five- and three-fold higher in women with moderate-severe anaemia (haemoglobin <100 g/l) at first visit and 28 weeks, respectively. These findings have clinical and public health importance. [ABSTRACT FROM AUTHOR]